Cilostazol, prepared according to the present invention, whose chemical name is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril, is known to be useful as an antithrombotic agent, a cerebral circulation improver, an anti-inflammatory agent, an antiulcer agent, a hypotensive agent, an antiasthmatic agent, and a phosphodiesterase inhibitor, etc. (see e.g. JP-A-56-49378).
As for the process for producing cilostazol, it is known a process comprising a reaction of a carbostyril derivative represented by the following general formula [II]:
with a tetrazole derivative represented by the following general formula [III]:
(wherein X represents a halogen atom), in the presence of an inorganic base or an organic base (see e.g. JP-A-56-49378 and Chem. Pharm. Bull., 31(4), 1151–1157 (1983)).
According to the above-mentioned known process, the yield of cilostazol is as low as about 50 to 74%, because there is also formed a compound in which the tetrazole derivative of general formula [III] has reacted not only with the hydroxyl group of the carbostyril derivative of general formula [II] but also with the 1-position of the cilostazol [I] simultaneously. The thus formed contaminative impurity, i.e. the compound in which the 1-position of the cilostazol [I] is substituted by the tetrazole derivative of general formula [III], is difficult to remove. Accordingly, there is a disadvantage of the known process that the production of the cilostazol with a high purity has required a complicated process of purification.
Another process for producing cilostazol, it is known a process comprising a reaction of the above-mentioned carbostyril derivative of the formula [II] with the above-mentioned tetrazole derivative of the formula [III], in the presence of a phase transfer catalyst (see e.g. JP-A-2001-213877 and WO 02/14283).
Yet another process for producing cilostazol, it is proposed a process comprising a reaction of the above-mentioned carbostyril derivative of the formula [II] with the above-mentioned tetrazole derivative of the formula [III], in a non-aqueous hydroxylic solvent in the presence of two kinds of basic compound or in a non-aqueous solvent in the presence of molecular sieves to scavenge water formed as a byproduct (see e.g. WO 02/14283).
However, these known processes inevitably use undesirable materials such as organic solvents and reagents in view of environmental hygiene. On the basis of the growing conscious to international environmental conservation in recent years, great demands become arisen in a chemical industry to make every effort decreasing use of the solvents and reagents pointed out the harmfulness, and preventing those materials from discharging into the environment. In order to fulfil those demands, established processes have to be down for a consideration, alternative raw materials, reagents and solvents being less harmful have to be found out, and the processes having higher conversion rate, yield and selectivity have to be developed; so that the environmental load can be diminished.
Under the circumstances with these social demands, the present inventors have made a study of the process being safer for the environment, for producing cilostazol with using water as a solvent in place of an organic solvent. Heretofore, the chemical reaction has been considered to be efficiently proceeding in the system wherein the reactive substances are dissolved. On the study of the process for producing cilostazol so far, water has never been used as a solvent, since the tetrazole derivative of the formula [III] is absolutely insoluble in water and the tetrazole derivative of the formula [III] is expected to be decomposed in water.
On the other hand, in view of the above-mentioned demands for the environmental hygiene, the present inventors have conducted further studies with the aim of establishing the process using water as a solvent by all means. As a result, the present inventors have found that the objective process is established by applying the specific conditions, and thereby the objects of the present invention can be achieved. Based on this finding, the present invention has been accomplished.